The present invention relates to adherable biomaterial patches, to methods of producing the patches, and more particularly to methods of using such patches, particularly in tissue repair.
Elastic fibers are responsible for certain elastic properties of tissues such as skin and lung, as well as arteries, and are composed of two morphologically distinct components, elastin and microfibrils. Microfibrils make up the quantitatively smaller component of the fibers and play an important role in elastic fiber structure and assembly.
The most abundant component of elastic fibers is elastin. The entropy of relaxation of elastin is responsible for the rubber-like elasticity of elastic fibers. Elastin is an extracellular matrix protein that is ubiquitous in mammals. Elastin is found, for example, in skin, blood vessels, and tissues of the lung where it imparts strength, elasticity and flexibility. In addition, elastin, which is prevalent in the internal elastic lamina (IEL) and external elastic lamina (EEL) of the normal artery, may inhibit the migration of smooth muscle cells into the intima.
In vertebrates elastin is formed through the secretion and crosslinking of tropoelastin, the 72-kDa biosynthetic precursor to elastin. This is discussed, for example, in an article entitled xe2x80x9cOxidation, Cross-linking, and Insolubilization of Recombinant Crosslinked Tropoelastin by Purified Lysyl Oxidasexe2x80x9d by Bedell-Hogan, et al in the Journal of Biological Chemistry, Vol. 268, No. 14, on pages 10345-10350 (1993).
As described in certain prior issued patents and in co-pending patent applications of one of the co-inventors herein, namely, U.S. Pat. No. 5,989,244 issued on Nov. 23, 1999, U.S. Pat. No. 5,990,379 issued on Nov. 23, 1999, U.S. Pat. No. 6,087,552 issued on Jul. 11, 2000 and U.S. Pat. No. 6,110,212 issued on Aug. 29, 2000, U.S. Ser. No. 09/000,604 filed on Dec. 30, 1997 all of which are incorporated herein by reference, elastin and elastin-based biomaterials, can be used in a number of medical applications.
These elastin and elastin-based biomaterials are typically sutured or fused to the tissue. Fusing is generally accomplished employing an energy absorbing material, and irradiating the energy absorbing material with light energy in a predetermined wavelength range with an intensity sufficient to facilitate the fusing operation.
Major life threatening injuries to areas of the human body, such as the gastrointestinal system, the pulmonary system, and the vascular system, require extensive surgical repairs, which may result in significant tissue loss, leading to morbidity and mortality. Certain areas of the body in particular, such as the gastrointestinal system and the lungs, require repairs which take into account the need for both flexibility and strength. Furthermore, the harsh environment of the gastrointestinal system, such as in the duodenum, is formed of acidic chyme from the stomach, pancreatic alkaline secretions, and a multitude of hormones and enzymes including proteases and lipases. The duodenum has the most severe conditions within the gastrointestinal system with pH extremes and digestive enzymes. Current treatments for injuries in these areas involves complex and lengthy surgeries with prolonged post-surgical drainage and delayed feeding.
Suturing and fusing of a patch onto a tissue substrate such as the lungs or in a highly acidic environment, such as the gastrointestinal system, the pulmonary system, and the vascular system, is both difficult and time consuming to complete. It is also a problem to maintain the patch in place for extended periods of time without incurring incidences of infection in the area which the repair has taken place. Suturing patches into the lung creates air leaks in the lung which can lead to lung collapse. Furthermore, laser fusion of patches can lead to unwanted thermal injury to the underlying lung tissue. Also, laser fusion of patches for the gastrointestinal system is typically not resistant to GI enzymes.
Adhesives for joining materials to human tissue are known. In order to be an acceptable in vivo adhesive for use in conjunction with lung or gastrointestinal applications, it must be non-toxic, non-inflamatory, sterilizable, biodegradable, flexible and exhibit certain strength properties. Prior art adhesives do not possess the above-described properties required for use in vivo in applications such as in the lungs or gastrointestinal system or leak sufficient resistance to acids and enzymes in during tissue substrate repair.
A biomaterial patch including a selected cyanoacrylate adhesive can effectively seal an injury of the gastrointestinal system, the pulmonary system, or the vascular system, thereby preventing leakage from that organ. The biomaterial patch, which consists essentially of elasin, or an elastin biomaterial, may serve as an effective physical and chemical barrier for repair of injuries which occur in the human body, particularly in portions of the body which can exhibit highly acidic environments. Typically, the biomaterial patch-tissue seal formed is water-tight and air-tight in nature. The biomaterial patches of the present invention meet the above-described use criteria, namely, they are non-toxic, non-inflamatory, sterilizable, biodegradable, flexible and exhibit excellent strength properties. The patch-tissue seal can be formed within minutes so that the repair procedure can be performed quickly and maintained in place during the healing process.
The subject biomaterial patch is relatively chemically inert. Therefore, it provides sufficient resistance to degradation by, if need be, highly acidic contents, to allow healing. By using a tissue adhesive as opposed to traditional sutures, such as a modified cyanoacrylate-based adhesive, the biomaterial patch can be quickly applied. Then, the patch of the present invention can typically achieve a fluid-tight or air-tight seal and thereby decrease the incidence of infection, air or fluid leaks that may be deleterious to haling and tissue health.
Other preferred properties of the patch are that it is sterilizable, minimally immunogenic, and resistant to digestive enzymes and acids. This combination of a biomaterial patch, and a tissue adhesive which can join the patch onto the tissue for a period of time sufficient to facilitate healing of the damaged tissue, can provide an innovative approach to repair of these injuries by decreasing post-operative complications, thereby increasing chances of full functional recovery.
This invention relates to a method for producing an adherable biomaterial patch. The subject patch is capable of being joined onto a tissue substrate. The invention is also directed to the patch per se, and to a method for producing the adherable biomaterial patch which is joined onto a tissue substrate. A preferred patch can even function in a highly acidic environment.
The method of the present invention comprises providing a biomaterial patch consisting essentially of elastin or an elastin-based biomaterial having at least one outer surface. Next, at least one outer surface of the biomaterial patch is treated with a selected cyanoacrylate adhesive to produce a adherable biomaterial patch.
The adherable biomaterial patch exhibits a Minimum Hold Time when joined onto the tissue substrate, typically a live tissue substrate, preferably in a highly acidic environment. This Minimum Hold Time is typically at least about 48 hours, preferably at least about 72 hours, more preferably at least about 96 hours, and most preferably at least about 7 days.
The biomaterial patch is typically unilaminar or bilaminar in nature, preferably bilaminar, where additional patch strength is desired. It also preferably forms a substantially water-tight seal, as well as a substantially air-tight seal, when joined onto a tissue substrate.
The method of the present invention can be conducted in an environment, when the adherable biomaterial patch joined onto the tissue substrate, which attains a highly acidic level. More specifically, the pH attained during the period in which the adherable biomaterial patch joined onto the tissue substrate is typically up to about 4.5, more typically up to about 5.0, and most typically up to about 6.0. Moreover, the tissue substrate can be the gastrointestinal system, or a portion thereof, such as the duedenum.
The adherable biomaterial patch has a Shear Strength (24 hour) which is preferably at least about 10 kPa, more preferably at least about 12 kPa, and most preferably at least about 15 kPa. The adherable biomaterial patch can have a Shear Strength (7 day) which is preferably at least about 10 kPa, more preferably at least about 12 kPa, and most preferably at least about 15 kPa.
Shear strength for the subject adherable biomaterial patch is measured using a Chatillon V1000 Mechanical Tester, as follows:
1. Prepare the sample by cutting it into two halves lengthwise.
2. Then overlap one end of the first half with one end of the second half. Ensuring that the two pieces are attached only within on the overlapped region as shown in the figure below. If gluing the 2 pieces, use 30 xcexcl of glue.
3. Measure the area of overlap of the two pieces using a calipers and record.
4. Choose a load cell and calibrate.
5. Using the load cell, zero the position and tare the force. Make sure that the grips are touching
6. Attach the sample to the grips, and move the upper grip until the sample is not sagging, is centered and aligned. At this point, make sure that the force is still 0xc2x10.025 g.
7. Acquire data at a 20 Hz frequency, 1 mm/sec stretch rate. Make sure that the tester is actually set to exert 100% of the load cell being used.
8. Open the data in Excel 98. Use the macro, GlueTestStart. Enter the measured overlap are (mm2) in cell C2.
9. Shear Stress (kPa) is calculated using Overlap area (lengthxc3x97width) for each sample.
The adherable biomaterial patch has a Flexibility which is preferably at least about 100 kPa, more preferably at least about 125 kPa, and most preferably at least about 150 kPa.
Flexibility for the subject adherable biomaterial patch is measured, using a Chatillon V1000 Mechanical Tester, as follows:
1. Measure the surface area of the sample using a calipers and record.
2. Choose a load cell and calibrate.
3. Using the load cell, zero the position and tare the force. Make sure that the grips are touching.
4. Attach the sample to the grips, and move the upper grip until the sample is not sagging, is centered and aligned. At this point, make sure that the force is still 00xc2x10.025 g.
5. Acquire data at a 20 Hz frequency, 1 mm/sec stretch rate, and fix the pull distance to about 2000 xcexcm (ensure sample does not break). Make sure that the tester is actually set to exert 100% of the load cell being used.
6. This initial pull of the sample gives its elastic modulus, which serves as a comparison against the combined modulus of the sample and the adhesive.
7. Coat one surface of the sample with the tissue adhesive 20xc2x15 xcexcl and allow the adhesive to dry. The drying sample should be placed in a moist, though not wet, environment to keep the elastin hydrated.
8. Once the adhesive is dry, measure its thickness as well as the sample width using calipers.
9. Repeat steps 4, 5 and 6. Make sure the pull distance is set to break the, sample.
10. Open the data for each of the two files, sample""s pre-stretch and the adhesive-coated sample, in Excel 98. Use the macro GlueTestStart. Enter the measured adhesive area (sample width (mm)xc3x97thickness (mm) in cell C2.
11. Elastic modulus (kPa) for both the pre-stretched sample, and the adhesive-coated sample is calculated as the slope of the linear portion of the curve.
The adherable biomaterial patch generally has cure rate which allows the user to join same in place in after the passage of a relatively sort period of time. Thus, the adherable biomaterial patch has a Minimum Cure Time of at not more than about 5 Minutes, preferably not more than about 4 Minutes, more preferably not more than about 3 Minutes.
The adhesive of this invention is typically a cyanoacrylate adhesive, preferably an alkoxyalkyl cyanoacrylate, more preferably a methoxyalkyl cyanoacrylate, and most preferably methoxypropyl cyanoacrylate. In a particularly preferred form of this invention, the cyanoacrylate adhesive further can include an additive which is typically a polymeric material. For example, an absorbable cyanoacrylate-based tissue adhesive, developed and manufactured by PolyMed, Inc. of Anderson, S.C., can be used to adhere the patch of this invention to the tissue. A preferred PolyMed adhesive which can be employed is denoted as GF-62 which comprises 95% by weight of methoxypropyl cyanoacrylate and 5% by weight of a solid miscible polymeric additive comprising a copolymer of caprolactone and glycolide. Another preferred PolyMed adhesive is GF-89B which comprises 97% by weight of methoxypropyl cyanoacrylate and 3% by weight of a solid miscible polymeric additive comprising VG3. The additive for the cyanoacrylate adhesive is typically provided in an amount up to about 5% by weight, preferably the amount of these additives is up to about 10% by weight, more preferably up to about 15% by weight, and most preferably up to about 20% by weight, based on the total weight of the cyanoacrylate and the additive, based on the total weight of the adhesive.
Further objects and advantages of the invention will be clear from the description that follows.